Simple isatin derivatives as free radical scavengers: Synthesis, biological evaluation and structure-activity relationship

To develop more potent small molecules with enhanced free radical scavenger properties, a series of N-substituted isatin derivatives was synthesized, and the cytoprotective effect on the apoptosis of PC12 cells induced by H2O2 was screened. All these compounds were found to be active, and N-ethyl isatin was found with the most potent activity of 69.7% protective effect on PC12 cells. Structure-activity relationship analyses showed the bioactivity of N-alkyl isatins decline as the increasing of the chain of the alkyl group, furthermore odd-even effect was found in the activity, which is interesting for further investigation

West Antarctic ice loss influenced by internal climate variability and anthropogenic forcing

Recent ice loss from the West Antarctic Ice Sheet has been caused by ocean melting of ice shelves in the Amundsen Sea. Eastward wind anomalies at the shelf break enhance the import of warm Circumpolar Deep Water onto the Amundsen Sea continental shelf, which creates transient melting anomalies with an approximately decadal period. No anthropogenic influence on this process has been established. Here, we combine observations and climate model simulations to suggest that increased greenhouse gas forcing caused shelf-break winds to transition from mean easterlies in the 1920s to the near-zero mean zonal winds of the present day. Strong internal climate variability, primarily linked to the tropical Pacific, is superimposed on this forced trend. We infer that the Amundsen Sea experienced decadal ocean ariability throughout the twentieth century, with warm anomalies gradually becoming more prevalent, offering a credible explanation for the ongoing ice loss. Existing climate model projections show that strong future greenhouse gas forcing creates persistent mean westerly shelf-break winds by 2100, suggesting a further enhancement of warm ocean anomalies. These wind changes are weaker under a scenario in which greenhouse gas concentrations are stabilized

Shared communication processes within healthcare teams for rare diseases and their influence on healthcare professionals' innovative behavior and patient satisfaction

<p>Abstract</p> <p>Background</p> <p>A rare disease is a pattern of symptoms that afflicts less than five in 10,000 patients. However, as about 6,000 different rare disease patterns exist, they still have significant epidemiological relevance. We focus on rare diseases that affect multiple organs and thus demand that multidisciplinary healthcare professionals (HCPs) work together. In this context, standardized healthcare processes and concepts are mainly lacking, and a deficit of knowledge induces uncertainty and ambiguity. As such, individualized solutions for each patient are needed. This necessitates an intensive level of innovative individual behavior and thus, adequate idea generation. The final implementation of new healthcare concepts requires the integration of the expertise of all healthcare team members, including that of the patients. Therefore, knowledge sharing between HCPs and shared decision making between HCPs and patients are important. The objective of this study is to assess the contribution of shared communication and decision-making processes in patient-centered healthcare teams to the generation of innovative concepts and consequently to improvements in patient satisfaction.</p> <p>Methods</p> <p>A theoretical framework covering interaction processes and explorative outcomes, and using patient satisfaction as a measure for operational performance, was developed based on healthcare management, innovation, and social science literature. This theoretical framework forms the basis for a three-phase, mixed-method study. Exploratory phase I will first involve collecting qualitative data to detect central interaction barriers within healthcare teams. The results are related back to theory, and testable hypotheses will be derived. Phase II then comprises the testing of hypotheses through a quantitative survey of patients and their HCPs in six different rare disease patterns. For each of the six diseases, the sample should comprise an average of 30 patients with six HCP per patient-centered healthcare team. Finally, in phase III, qualitative data will be generated via semi-structured telephone interviews with patients to gain a deeper understanding of the communication processes and initiatives that generate innovative solutions.</p> <p>Discussion</p> <p>The findings of this proposed study will help to elucidate the necessity of individualized innovative solutions for patients with rare diseases. Therefore, this study will pinpoint the primary interaction and communication processes in multidisciplinary teams, as well as the required interplay between exploratory outcomes and operational performance. Hence, this study will provide healthcare institutions and HCPs with results and information essential for elaborating and implementing individual care solutions through the establishment of appropriate interaction and communication structures and processes within patient-centered healthcare teams.</p

Evidence of an active volcanic heat source beneath the Pine Island Glacier

Tectonic landforms reveal that the West Antarctic Ice Sheet (WAIS) lies atop a major volcanic rift system. However, identifying subglacial volcanism is challenging. Here we show geochemical evidence of a volcanic heat source upstream of the fast-melting Pine Island Ice Shelf, documented by seawater helium isotope ratios at the front of the Ice Shelf cavity. The localization of mantle helium to glacial meltwater reveals that volcanic heat induces melt beneath the grounded glacier and feeds the subglacial hydrological network crossing the grounding line. The observed transport of mantle helium out of the Ice Shelf cavity indicates that volcanic heat is supplied to the grounded glacier at a rate of ~ 2500 ± 1700 MW, which is ca. half as large as the active Grimsvötn volcano on Iceland. Our finding of a substantial volcanic heat source beneath a major WAIS glacier highlights the need to understand subglacial volcanism, its hydrologic interaction with the marine margins, and its potential role in the future stability of the WAIS

Adaptive Evolution of Escherichia coli to an α-Peptide/β-Peptoid Peptidomimetic Induces Stable Resistance.

Antimicrobial peptides (AMPs) and synthetic analogues thereof target conserved structures of bacterial cell envelopes and hence, development of resistance has been considered an unlikely event. However, recently bacterial resistance to AMPs has been observed, and the aim of the present study was to determine whether bacterial resistance may also evolve against synthetic AMP analogues, e.g. α-peptide/β-peptoid peptidomimetics. E. coli ATCC 25922 was exposed to increasing concentrations of a peptidomimetic (10 lineages), polymyxin B (10 lineages), or MilliQ water (4 lineages) in a re-inoculation culturing setup covering approx. 500 generations. All 10 lineages exposed to the peptidomimetic adapted to 32 × MIC while this occurred for 8 out of 10 of the polymyxin B-exposed lineages. All lineages exposed to 32 × MIC of either the peptidomimetic or polymyxin B had a significantly increased MIC (16-32 ×) to the selection agent. Five transfers (≈ 35 generations) in unsupplemented media did not abolish resistance indicating that resistance was heritable. Single isolates from peptidomimetic-exposed lineage populations displayed MICs against the peptidomimetic from wild-type MIC to 32 × MIC revealing heterogeneous populations. Resistant isolates showed no cross-resistance against a panel of membrane-active AMPs. These isolates were highly susceptible to blood plasma antibacterial activity and were killed when plasma concentrations exceeded ≈ 30%. Notably, MIC of the peptidomimetic against resistant isolates returned to wild-type level upon addition of 25% plasma. Whole-genome sequencing of twenty isolates from four resistant lineages revealed mutations, in murein transglycosylase D (mltD) and outer-membrane proteins, which were conserved within and between lineages. However, no common resistance-conferring mutation was identified. We hypothesise that alterations in cell envelope structure result in peptidomimetic resistance, and that this may occur via several distinct mechanisms. Interestingly, this type of resistance result in a concomitant high susceptibility towards plasma, and therefore the present study does not infer additional concern for peptidomimetics as future therapeutics

ARHGEF7 (BETA-PIX) Acts as Guanine Nucleotide Exchange Factor for Leucine-Rich Repeat Kinase 2

Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson’s disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Methodology/Principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7. Conclusions/Significance: Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation. A newly identified familial mutation N1437S, localized within the GTPase domain of LRRK2, further underlines the importance of the GTPas

Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis

Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment

Using a community-based definition of poverty for targeting poor households for premium subsidies in the context of a community health insurance in Burkina Faso

Background: One of the biggest challenges in subsidizing premiums of poor households for community health insurance is the identification and selection of these households. Generally, poverty assessments in developing countries are based on monetary terms. The household is regarded as poor if its income or consumption is lower than a predefined poverty cut-off. These measures fail to recognize the multi-dimensional character of poverty, ignoring community members? perception and understanding of poverty, leaving them voiceless and powerless in the identification process. Realizing this, the steering committee of Nouna's health insurance devised a method to involve community members to better define `perceived? poverty, using this as a key element for the poor selection. The community-identified poor were then used to effectively target premium subsidies for the insurance scheme. Methods: The study was conducted in the Nouna's Health District located in northwest Burkina Faso. Participants in each village were selected to take part in focus-group discussions (FGD) organized in 41 villages and 7 sectors of Nouna's town to discuss criteria and perceptions of poverty. The discussions were audio recorded, transcribed and analyzed in French using the software NVivo 9. Results: From the FGD on poverty and the subjective definitions and perceptions of the community members, we found that poverty was mainly seen as scarcity of basic needs, vulnerability, deprivation of capacities, powerlessness, voicelessness, indecent living conditions, and absence of social capital and community networks for support in times of need. Criteria and poverty groups as described by community members can be used to identify poor who can then be targeted for subsidies. Conclusion: Policies targeting the poorest require the establishment of effective selection strategies. These policies are well-conditioned by proper identification of the poor people. Community perceptions and criteria of poverty are grounded in reality, to better appreciate the issue. It is crucial to take these perceptions into account in undertaking community development actions which target the poor. For most community-based health insurance schemes with limited financial resources, using a community-based definition of poverty in the targeting of the poorest might be a less costly alternative